Aminopyrimidines useful as inhibitors of protein kinases

ABSTRACT

The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders. The invention also provides processes for preparing the compounds of the invention.

BACKGROUND OF THE INVENTION

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase comprised of α and β isoforms that are each encoded by distinct genes [Coghlan et al., Chemistry & Biology 2000, 7, 793-803; and Kim and Kimmel, Curr. Opinion Genetics Dev., 2000 10, 508-514]. GSK-3 has been implicated in various diseases, disorders, and conditions including diabetes, Alzheimer's disease, CNS diseases such as bipolar disorder, schizophrenia , cerebral stroke, Huntington's and other neurodegenerative diseases, leukocytopenia and cardiomyocyte hypertrophy [PCT Application Nos.: WO 99/65897 and WO 00/38675; and Haq et al., J. Cell Biol. 2000, 151, 117-130]. These diseases, disorders, and conditions are associated with the abnormal operation of certain cell signaling pathways in which GSK-3 plays a role. GSK-3 has been found to phosphorylate and modulate the activity of a number of regulatory proteins. These proteins include glycogen synthase, which is the rate limiting enzyme necessary for glycogen synthesis, the microtubule associated protein Tau, the gene transcription factor β-catenin, the translation initiation factor e1F2B, as well as ATP citrate lyase, axin, heat shock factor-1, c-Jun, c-myc, c-myb, CREB, and CEPBA. These diverse protein targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation, and development.

In a GSK-3 mediated pathway that is relevant for the treatment of type II diabetes, insulin-induced signaling leads to cellular glucose uptake and glycogen synthesis. Along this pathway, GSK-3 is a negative regulator of the insulin-induced signal. Normally, the presence of insulin causes inhibition of GSK-3 mediated phosphorylation and deactivation of glycogen synthase. The inhibition of GSK-3 leads to increased glycogen synthesis and glucose uptake [Klein et al., PNAS 1996, 93, 8455-8459; Cross et al., Biochem. J. 1994, 303, 21-26); Cohen, Biochem. Soc. Trans. 1993, 21, 555-567; and Massillon et al., Biochem J. 1994, 299, 123-128]. However, in a diabetic patient, where the insulin response is impaired, glycogen synthesis and glucose uptake fail to increase despite the presence of relatively high blood levels of insulin. This leads to abnormally high blood levels of glucose with acute and long-term effects that may ultimately result in cardiovascular disease, renal failure and blindness. In such patients, the normal insulin-induced inhibition of GSK-3 fails to occur. It has also been reported that in patients with type II diabetes, GSK-3 is overexpressed [see, PCT Application: WO 00/38675]. Therapeutic inhibitors of GSK-3 are therefore potentially useful for treating diabetic patients suffering from an impaired response to insulin.

GSK-3 activity is associated with Alzheimer's disease. The hallmarks of this disease are the extracellular plaques formed by aggregated β-amyloid peptides and the formation of intracellular neurofibrillary tangles via the tau protein.

It has been shown that GSK-3 inhibition reduces amyloid-β peptides in an animal model of Alzheimer's disease. See pages 435, 438. Phiel et. al., Nature 423, 435-439 (2003). Mice over-expressing amyloid precursor protein (APP) treated with lithium (a GSK-3α inhibitor) over a three-week period showed over a 50% decrease in amyloid-β peptide tissue levels.

The neurofibrillary tangles contain hyperphosphorylated Tau protein, in which Tau is phosphorylated on abnormal sites. GSK-3 is known to phosphorylate these abnormal sites in cell and animal models. Conditional transgenic mice that over-express GSK-3 develop aspects of AD including tau hyperphosphorylation, neuronal apoptosis and spatial learning deficit. Turning off GSK-3 in these mice restores normal behavior, reduces Tau hyperphosphorylation and neuronal apoptosis. (Engel T et al., J Neuro Sci, 2006, 26, 5083-5090 and Lucas et al, EMBO J, 2001, 20, 27-39) Inhibitors of GSK-3 have also been shown to prevent hyperphosphorylation of Tau in cells [Lovestone et al., Current Biology 1994, 4, 1077-86; and Brownlees et al., Neuroreport 1997, 8, 3251-55].

GSK-3 as a target for psychosis and mood disorders, such as schizophrenia and bipolar disease, respectively, have been reported in the literature. AKT haplotype deficiency was identified in a subset of schizophrenic patients which correlated with increased GSK-3 activity. A single allele knockout of GSK-3β resulted in attenuated hyperactivity in response to amphetamine in a behavior model of mania.

Several antipsychotic drugs and mood stabilizers used to treat both schizophrenic and bipolar patients have been shown to inhibit GSK-3 (Emamian et al, Nat Genet, 2004, 36, 131-137; Obrien et al, J Neurosci, 2004, 24, 6791-6798; Beaulieu et al, PNAS, 2004, 101, 5099-5104; Li et al Int j Neuropsychopharmacol, 2006, pp 1-13; Gould T D, Expert Opin Ther Targets, 2006, 10, 377-392). Furthermore, a recent patent publication, US 2004/0039007, describes GSK-3 inhibitors that show anti-schizophrenic and anxiolytic effects in relevant mouse behavior models.

GSK-3 activity is associated with stroke. Wang et al. showed that IGF-1 (insulin growth factor-1), a known GSK-3 inhibitor, reduced infarct size in rat brains after transient middle cerebral artery occlusion (MCAO), a model for stroke in rats. [Wang et al., Brain Res 2000, 859, 381-5; Sasaki et al., Neurol Res 2001, 23, 588-92; Hashimoto et al., J. Biol. Chem 2002, 277, 32985-32991]. US 2004/0039007 describes the effect of GSK-3 inhibitors in MCAO, a stroke model in rats. These GSK-3 inhibitors significantly reduced striatal ischemic damage and reduce edema formation in rats. Additionally, the rats “demonstrated marked improvement in neurological function over the time course of the experiment.”

Inhibition of GSK-3 activity has been linked to stem cell proliferation, differentiation and neuronal plasticity Inhibitors of GSK-3 have been shown to sustain self-renewal of embryonic stem cells, promote neuron, beta-cell, myeloid and osteoblast differentiation. (Sato et al, Nature Medicine 10, 55-63, 2004; Ding et al PNAS 100, 7632-37, 2003; Branco et al J Cell Science 117, 5731-37, 2004; Trowbridge et al, Nature Medicine 12, 89-98, 2006; Mussmann et al, JBC (Epub ahead of print)2007; Kulkarni et al Journal of Bone and Mineral Res. 21, 910-920, 2006) With respect to neuronal plasticity, inhibition of GSK-3 has been shown to be important for regulating polarity, long-term potentiation (LTP) and neurite/axon growth (Hooper et al European J of Neuroscience 25, 81-86, 2007; Kim et al, Neuron 52, 981-996, 2006; Jiang et al Cell 120, 123-135, 2005;). Taken all together, GSK-3 small-molecule inhibitors have the potential to act as chemomodulators of cell differentiation and plasticity which has implications for many types of degenerative conditions such as Neurodegenerative diseases (Stroke, Alzheimer, Parkinson, Huntington, ALS and Multiple Sclerosis), Leukocytopenia, Diabetes and Osteoporosis.

Accordingly, there is a great need to develop compounds useful as inhibitors of protein kinases. In particular, it would be desirable to develop compounds that are useful as inhibitors of GSK-3, particularly given the inadequate treatments currently available for the majority of the disorders implicated in their activation.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I:

wherein the variables are as defined herein.

The present invention also provides processes for preparing these compounds, compositions, pharmaceutical compositions, and methods of using such compounds and compositions for inhibiting protein kinases. These compounds are particularly useful as GSK-3 inhibitors.

These compounds and pharmaceutically acceptable compositions thereof are useful for treating or preventing a variety of diseases, disorders or conditions, including, but not limited to, an autoimmune, inflammatory, proliferative, or hyperproliferative disease, a neurodegenerative disease, or an immunologically-mediated disease.

The compounds provided by this invention are also useful for the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides compounds of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Ht is

-   -   Ring D is a 4-7 membered monocyclic ring or 8-10 membered         bicyclic ring selected from a heterocyclyl or a carbocyclyl         ring; said heterocyclyl ring having 1-4 ring heteroatoms         selected from nitrogen, oxygen or sulfur, wherein each         substitutable ring carbon of Ring D is independently substituted         with oxo or —R⁵, and any substitutable ring nitrogen is         independently substituted with —R⁴;     -   X is sulfur, oxygen, or NR^(2′);     -   Y is nitrogen or CR₂;     -   Z¹ and Z² are each independently N or CR⁹; provided that at         least one of Z¹ or Z² is N;     -   R^(X) is T¹-R³;     -   R^(Y) is T²-R¹⁰;     -   R² and R^(2′) are independently selected from —R or -T³-W—R⁶; or         R² and R^(2′) are taken together with their intervening atoms to         form a fused, 5-8 membered, unsaturated or partially         unsaturated, ring having 0-3 ring heteroatoms selected from         nitrogen, oxygen, or sulfur, wherein each substitutable carbon         on said fused ring formed by R² and R^(2′) is substituted with         halo, oxo, —CN, —NO₂, —R₇, or —V—R⁶, and any substitutable         nitrogen on said ring formed by R² and R^(2′) is substituted         with R⁴;     -   each T, T¹ and T³ is independently a bond or a C₁₋₄ alkylidene         chain;     -   T² is independently a bond or a C₁₋₄ alkylidene chain wherein up         to three methylene units of the alkylidene chain are optionally         replaced by —O—, —C(═O)—, —S(O)—, —S(O)₂—, —S—, or —N(R₄)—;     -   R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR,         —COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,         —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂R″, —N(R⁴)N(R⁴)₂,         —C(═NH)N(R⁴)₂, —C(═NH)—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,         —N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;     -   each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂         (optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷,         or two R⁴ on the same nitrogen are taken together to form a 3-8         membered heterocyclyl or heteroaryl ring;     -   each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,         —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂,         —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂R″,         —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,         —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;     -   V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,         —CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—,         —N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—,         —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,         —C(R⁶)₂N(R₆)—, —C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—,         —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,         —C(R⁶)₂N(R⁶)SO₂N(R₆)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;     -   W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,         —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)₂OC(O)—,         —C(R⁶)₂OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—,—C(R⁶)₂N(R⁶)C(O)O—,         —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,         —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;     -   each R⁶ is independently selected from hydrogen or C₁₋₄         aliphatic group optionally substituted with 0-3 J⁶; or two R⁶         groups on the same nitrogen atom are taken together with the         nitrogen atom to form a 4-6 membered heterocyclyl or heteroaryl         ring, wherein said heterocyclyl or heteroaryl ring is optionally         substituted with 0-4 J⁶;     -   each R⁷ is independently selected from hydrogen or R″; or two R⁷         on the same nitrogen are taken together with the nitrogen to         form a 4-8 membered heterocyclyl or heteroaryl ring, wherein         said heterocyclyl or heteroaryl ring is optionally substituted         with 0-4 J⁷;     -   each R⁹ is —R′, -halo, —OR′, —C(═O)R′, —CO₂R′, —COCOR′,         COCH₂COR′, —NO₂, —CN, —S(O)R′, —S(O)₂R′, —SR′, —N(R′)₂,         —CON(R′)₂, —SO₂N(R′)₂, —OC(═O)R′, —N(R′)COR′,—N(R′)CO₂(C₁₋₆         aliphatic), —N(R′)N(R′)₂, —N(R′)CON(R′)₂, —N(R′)SO₂N(R′)₂,         —N(R′)SO₂R′, —OC(═O)N(R′)₂, ═NN(R′)₂, ═N—OR′, or ═O;     -   each R¹⁰ is a 4-membered heterocyclic ring containing 1-2         heteroatoms selected from O, NR¹¹, and S; each R¹⁰ is optionally         substituted with 0-3 occurrences of J;     -   each R¹¹, is —R⁷, —COR⁷, —CO₂ (optionally substituted C₁₋₆         aliphatic), —CON(R⁷)₂, or —SO₂R⁷;     -   each R is independently selected from hydrogen or an optionally         substituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a         heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring         having 4-10 ring atoms; each R is optionally substituted with         0-5 R⁹;     -   each R′ is independently hydrogen or a C₁₋₆ aliphatic group         optionally substituted with 0-4 J′; or two R′, together with the         atom(s) to which they are attached, form a 3-6 membered         carbocyclyl or heterocyclyl wherein said carbocyclyl or         heterocyclyl is optionally substituted with 0-4 J′;     -   each R″ is independently C₁₋₆ aliphatic optionally substituted         with 0-4 J″;     -   each J′ and J″ is independently NH₂, NH(C₁₋₄aliphatic),         N(C₁₋₄aliphatic)₂, halogen, C₁₋₄aliphatic, OH, O(C₁₋₄aliphatic),         NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄ aliphatic), or         haloC₁₋₄aliphatic;     -   each J, J⁶, and J⁸ is independently -halo, —OR, oxo, C₁₋₆         aliphatic, —C(═O)R, —CO₂R, —COCOR, COCH₂COR, —NO₂, —CN, —S(O)R,         —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂, —OC(═O)R,         —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, ═NN(R⁴)₂,         ═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or         —OC(═O)N(R⁷)₂;     -   each J⁷ is independently -halo, —OR, oxo, C₁₋₆ aliphatic,         —C(═O)R, —CO₂R, —COCOR, COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R,         —SR, —N(R¹²)₂, —CON(R¹²)₂, —SO₂N(R¹²)₂, —OC(═O)R, —N(R¹²)COR,         —N(R¹²)CO₂(C₁₋₆ aliphatic), —N(R¹²)N(R²)₂, ═NN(R¹²)₂, ═N—OR,         —N(R¹²)CON(R¹²)₂, —N(R¹²)SO₂N(R¹²)₂, —N(R¹²)SO₂R, or         —OC(═O)N(R¹²)₂; or     -   2 J groups, 2 J⁶ groups, 2 J⁷ groups, or 2 J⁸ groups, on the         same atom or on different atoms, together with the atom(s) to         which they are bound, form a 3-8 membered saturated, partially         saturated, or unsaturated ring having 0-2 heteroatoms selected         from O, N, or S;     -   R¹² is independently selected from hydrogen or R″; or two R₁₂ on         the same nitrogen are taken together with the nitrogen to form a         4-8 membered heterocyclyl or heteroaryl ring, wherein said         heterocyclyl or heteroaryl ring is optionally substituted with         0-4 J″.

Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

As described herein, a specified number range of atoms includes any integer therein. For example, a group having from 1-4 atoms could have 1, 2, 3, or 4 atoms.

As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” In general, the term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.

The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or cyclic, branched or unbranched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl, n-butenyl, ethynyl, and tert-butyl.

The term “cycloaliphatic” (or “carbocycle” or “carbocyclyl” or “cycloalkyl”) refers to a monocyclic C₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl and cycloalkenyl groups. Specific examples include, but are not limited to, cyclohexyl, cyclopropenyl, and cyclobutyl.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members are an independently selected heteroatom. In some embodiments, the “heterocycle”, “heterocyclyl”, or “heterocyclic” group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members.

Suitable heterocycles include, but are not limited to, 3-1H-benzimidazol-2—One, 3-(1-alkyl)-benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane, benzodithiane, and 1,3-dihydro-imidazol-2-one.

Cyclic groups, (e.g. cycloaliphatic and heterocycles), can be linearly fused, bridged, or spirocyclic.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, or phosphorus, (including, any oxidized form of nitrogen, sulfur, or phosphorus; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The terms “haloalkyl”, “haloalkenyl”, “haloaliphatic”, and “haloalkoxy” mean alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The terms “halogen”, “halo”, and “hal” mean F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. The term “aryl” also refers to heteroaryl ring systems as defined hereinbelow.

The term “heteroaryl”, used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic, or tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”. Suitable heteroaryl rings include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

The term “protecting group” and “protective group” as used herein, are interchangeable and refer to an agent used to temporarily block one or more desired reactive sites in a multifunctional compound. In certain embodiments, a protecting group has one or more, or preferably all, of the following characteristics: a) is added selectively to a functional group in good yield to give a protected substrate that is b) stable to reactions occurring at one or more of the other reactive sites; and c) is selectively removable in good yield by reagents that do not attack the regenerated, deprotected functional group. Exemplary protecting groups are detailed in Greene, T. W., Wuts, P. G in “Protective Groups in Organic Synthesis”, Third Edition, John Wiley & Sons, New York: 1999 (and other editions of the book), the entire contents of which are hereby incorporated by reference. The term “nitrogen protecting group”, as used herein, refers to an agents used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound. Preferred nitrogen protecting groups also possess the characteristics exemplified above, and certain exemplary nitrogen protecting groups are also detailed in Chapter 7 in Greene, T. W., Wuts, P. G in “Protective Groups in Organic Synthesis”, Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.

In some embodiments, one of more methylene units in an alkyl or aliphatic chain can be optionally replaced with another atom or group. Examples of such atoms or groups would include, but are not limited to, —NR—, —O—, —S—, —CO₂—, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NR—, —C(═N—CN), —NRCO—, —NRC(O)O—, —SO₂NR—, —NRSO₂—, —NRC(O)NR—, —OC(O)NR—, —NRSO₂NR—, —SO—, or —SO₂—, wherein R is defined herein.

Unless otherwise specified, the optional replacements form a chemically stable compound. Optional replacements can occur both within the chain and at either end of the chain; i.e. both at the point of attachment and/or also at the terminal end. Two optional replacements can also be adjacent to each other within a chain so long as it results in a chemically stable compound. The optional replacements can also completely replace all of the carbon atoms in a chain. For example, a C₃ aliphatic can be optionally replaced by —NR—, —C(O)—, and —NR— to form —NRC(O)NR— (a urea).

Unless otherwise specified, if the replacement occurs at the terminal end, the replacement atom is bound to a hydrogen atom on the terminal end. For example, if a methylene unit of —CH₂CH₂CH₃ were optionally replaced with —O—, the resulting compound could be —OCH₂CH₃, —CH₂OCH₃, or —CH₂CH₂OH.

Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

Unless otherwise indicated, a substituent can freely rotate around any rotatable bonds. For example, a substituent drawn as

also represents

Additionally, unless otherwise indicated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

It will also be appreciated that the compounds of the present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable salt, salts, or mixtures thereof.

As used herein, the term “pharmaceutically acceptable salt” refers to salts of a compound which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds. Acid addition salts can be prepared by 1) reacting the purified compound in its free-based form with a suitable organic or inorganic acid and 2) isolating the salt thus formed.

Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

Base addition salts can be prepared by 1) reacting the purified compound in its acid form with a suitable organic or inorganic base and 2) isolating the salt thus formed. Base addition salts include alkali or alkaline earth metal salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. Other acids and bases, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid or base addition salts.

The following abbreviations are used:

-   LiHMDS Lithium Hexamethyldisilazide -   DCM dichloromethane -   EtOAc ethyl acetate -   DMSO dimethyl sulfoxide -   ATP adenosine triphosphate -   DTT dithiothreitol -   NMR nuclear magnetic resonance -   HPLC high performance liquid chromatography -   LCMS liquid chromatography-mass spectrometry -   TLC thin layer chromatography -   Rt retention time

One embodiment provides a compound of formula I

or a pharmaceutically acceptable salt thereof, wherein: Ht is

Ring D is a 4-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from a heterocyclyl or a carbocyclyl ring; said heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted with oxo or —R⁵, and any substitutable ring nitrogen is independently substituted with —R⁴;

-   -   X is sulfur, oxygen, or NR^(2′);     -   Y is nitrogen or CR₂;     -   Z¹ and Z² are each independently N or CR⁹; provided that at         least one of Z¹ or Z² is N;     -   R^(X) is T¹-R³;     -   R^(Y) is T²-R¹⁰;     -   R² and R^(2′) are independently selected from —R or -T³-W—R⁶; or         R² and R^(2′) are taken together with their intervening atoms to         form a fused, 5-8 membered, unsaturated or partially         unsaturated, ring having 0-3 ring heteroatoms selected from         nitrogen, oxygen, or sulfur, wherein each substitutable carbon         on said fused ring formed by R² and R^(2′) is substituted with         halo, oxo, —CN, —NO₂, —R₇, or —V—R⁶, and any substitutable         nitrogen on said ring formed by R² and R^(2′) is substituted         with R⁴;     -   each T, T¹ and T³ is independently a bond or a C₁₋₄ alkylidene         chain;     -   T² is independently a bond or a C₁₋₄ alkylidene chain wherein up         to three methylene units of the alkylidene chain are optionally         replaced by —O—, —C(═O)—, —S(O)—, —S(O)₂—, —S—, or —N(R₄)—;     -   R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR,         —COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,         —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂R″, —N(R⁴)N(R⁴)₂,         —C(═NH)N(R⁴)₂, —C(═NH)—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,         —N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;     -   each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂         (optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷,         or two R⁴ on the same nitrogen are taken together to form a 3-8         membered heterocyclyl or heteroaryl ring;     -   each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,         —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂,         —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂R″,         —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,         —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;     -   V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,         —CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—,         —N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—,         —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,         —C(R⁶)₂N(R₆)—, —C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—,         —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,         —C(R⁶)₂N(R⁶)SO₂N(R₆)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;     -   W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,         —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)₂OC(O)—,         —C(R⁶)₂OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—,—C(R⁶)₂N(R⁶)C(O)O—,         —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,         —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;     -   each R⁶ is independently selected from hydrogen or C₁₋₄         aliphatic group optionally substituted with 0-3 J⁶; or two R⁶         groups on the same nitrogen atom are taken together with the         nitrogen atom to form a 4-6 membered heterocyclyl or heteroaryl         ring, wherein said heterocyclyl or heteroaryl ring is optionally         substituted with 0-4 J⁶;     -   each R⁷ is independently selected from hydrogen or R″; or two R⁷         on the same nitrogen are taken together with the nitrogen to         form a 4-8 membered heterocyclyl or heteroaryl ring, wherein         said heterocyclyl or heteroaryl ring is optionally substituted         with 0-4 J⁷;     -   each R⁹ is —R′, -halo, —OR′, —C(═O)R′, —CO₂R′, —COCOR′,         COCH₂COR′, —NO₂, —CN, —S(O)R′, —S(O)₂R′, —SR′, —N(R′)₂,         —CON(R′)₂, —SO₂N(R′)₂, —OC(═O)R′, —N(R′)COR′,—N(R′)CO₂(C₁₋₆         aliphatic), —N(R′)N(R′)₂, —N(R′)CON(R′)₂, —N(R′)SO₂N(R′)₂,         —N(R′)SO₂R′, —OC(═O)N(R′)₂, ═NN(R′)₂, ═N—OR′, or ═O;     -   each R¹⁰ is a 4-membered heterocyclic ring containing 1-2         heteroatoms selected from O, NR¹¹, and S; each R¹⁰ is optionally         substituted with 0-3 occurrences of J;     -   each R¹¹, is —R⁷, —COR⁷, —CO₂ (optionally substituted C₁₋₆         aliphatic), —CON(R⁷)₂, or —SO₂R⁷;     -   each R is independently selected from hydrogen or an optionally         substituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a         heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring         having 4-10 ring atoms; each R is optionally substituted with         0-5 R⁹;     -   each R′ is independently hydrogen or a C₁₋₆ aliphatic group         optionally substituted with 0-4 J′; or two R′, together with the         atom(s) to which they are attached, form a 3-6 membered         carbocyclyl or heterocyclyl wherein said carbocyclyl or         heterocyclyl is optionally substituted with 0-4 J′;     -   each R″ is independently C₁₋₆ aliphatic optionally substituted         with 0-4 J″;     -   each J′ and J″ is independently NH₂, NH(C₁₋₄aliphatic),         N(C₁₋₄aliphatic)₂, halogen, C₁₋₄aliphatic, OH, O(C₁₋₄aliphatic),         NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄ aliphatic), or         haloC₁₋₄aliphatic;     -   each J, J⁶, and J⁸ is independently -halo, —OR, oxo, C₁₋₆         aliphatic, —C(═O)R, —CO₂R, —COCOR, COCH₂COR, —NO₂, —CN, —S(O)R,         —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂, —OC(═O)R,         —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, ═NN(R⁴)₂,         ═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or         —OC(═O)N(R⁷)₂;     -   2 J groups, 2 J⁶ groups, 2 J⁷ groups, or 2 J⁸ groups, on the         same atom or on different atoms, together with the atom(s) to         which they are bound, form a 3-8 membered saturated, partially         saturated, or unsaturated ring having 0-2 heteroatoms selected         from O, N, or S.

In some embodiments of this invention, Ht is

In some embodiments, Ht is

In other embodiments, Ht is

In another embodiment of this invention, X is S. In another embodiment, X is NR^(2′). In some embodiments, Y is N or CR². In other embodiments, Y is N. In yet other embodiments, Y is CR². In some embodiments, X is S and Y is N. In other embodiments, X is S and Y is CR².

In some embodiments, T² is independently a bond or a C₁₋₄ alkylidene chain wherein up to three methylene units of the alkylidene chain are optionally replaced by —O—, —C(═O)—, —S(O)—, —S(O)₂—, —S—, or —N(R⁴) —; In some embodiments, said optional replacements in the methylene units of T are selected from —CO₂—, —COCO—, —COCH₂CO—, —S(O)—, —S(O)₂—, —S—, —N(R⁴)—, —CON(R⁷)—, —SO₂N(R⁷) —, —OC(═O)—, —N(R⁷)CO—, —N(R⁷)CO₂—, —N(R⁴)N(R⁴)—, —N(R⁷)CON(R⁷)—, —N(R⁷)SO₂N(R₇)—, —N(R⁴)SO₂—, or —OC(═O)N(R⁷⁾—.

In some embodiments of this invention, Z¹ and Z² are both nitrogen. In other embodiments, Z¹ is CR⁹ and Z² is nitrogen. In yet other embodiments, Z¹ is nitrogen and Z² is CH.

In some embodiments of this invention, R_(2′) is hydrogen or methyl. In some embodiments, R^(2′) is hydrogen.

In other embodiments, R₂ is T3-W—R₆ or R; wherein W is —C(R⁶)₂O—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)₂OC(O) —, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, or —CON(R⁶)—, and R is an optionally substituted group selected from C₁₋₆ aliphatic or phenyl. In yet other embodiments, R² is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group. In some embodiments, R₂ is hydrogen or a substituted or unsubstituted group selected from aryl or a C₁₋₆ aliphatic group.

In some embodiments of this invention, R₂ and R_(2′) are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring. In other embodiments, R₂ and R_(2′) are taken together with their intervening atoms to form a substituted or unsubstituted benzo or pyrido ring. In some embodiments, said benzo or pyrido ring is substituted with 1-2 halo substituents.

In another aspect of this invention, R^(X) is hydrogen, C₁₋₄aliphatic, or halo. In some embodiments, R^(X) is hydrogen, fluoro, methyl, ethyl, cyclopropyl, or isopropyl. In other embodiments, R^(X) is hydrogen.

In another aspect of this invention, R^(Y) is represented by formula ii-a:

In yet another aspect of this invention, R^(Y) is T²-R¹⁰ wherein T² is a bond. In some embodiments, R¹⁰ is an optionally substituted azetidine.

In yet another aspect of this invention, R^(Y) is represented by formula i:

In yet another aspect of this invention, R^(Y) is represented by formula iii:

In some embodiments, R¹¹ is H.

In one aspect of this invention, Ring D is an optionally substituted ring selected from piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, or isoquinolinyl. In some embodiments, Ring D is optionally substituted tetrahydronaphthyl, benzodioxinyl, indanyl, indolinyl, or isoquinolinyl. In some embodiments, Ring D is 5-8 membered cycloalkyl. In some embodiments, Ring D is cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, Ring D is cyclohexyl.

In another aspect of this invention, R¹ is -halo, an optionally substituted C₁₋₆ aliphatic group, phenyl, —COR⁶, —OR⁶, —CN, —SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or —NHSO₂R⁶. In some embodiments, R¹ is -halo, a C₁₋₆ haloaliphatic group, an optionally substituted C₁₋₆ aliphatic group, phenyl, or —CN. In other embodiments, R¹ is -halo, a C₁₋₄ aliphatic group optionally substituted with halogen, or —CN.

In some embodiments, each J, J⁶, and J⁸ is independently -halo, —OR, oxo, C₁₋₆ aliphatic, —C(═O) R, —CO₂R, —COCOR, COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, =NN(R⁴)₂, ═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or —OC(═O) N(R⁷)₂;

In some embodiments, each J⁷ is independently -halo, —OR, oxo, C₁₋₆ aliphatic, —C(═O)R, —CO₂R, —COCOR, COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R¹²)₂, —CON(R₁₂)₂, —SO₂N(R¹²)₂, —OC(═O)R, —N(R¹²)COR, —N(R¹²)CO₂ (C₁₋₆ aliphatic), —N(R¹³)N(R¹²)₂, ═NN(R¹²)₂, ═N—OR, —N(R₁₂)CON(R¹²)₂, —N(R¹²)SO₂N(R₁₂)₂, —N(R₁₂)SO₂R, or —OC(═O)N(R¹²)₂; wherein R₁₂ is independently selected from hydrogen or R″; or two R₁₂ on the same nitrogen are taken together with the nitrogen to form a 4-8 membered heterocyclyl or heteroaryl ring, wherein said heterocyclyl or heteroaryl ring is optionally substituted with 0-4 J”.

In some embodiments, two R₄ on the same nitrogen are taken together to form a 3-8 membered heterocyclyl or heteroaryl ring. In other embodiments, each R⁴ is independently selected from —R⁷, —COR₂ (optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷. In some embodiments, said C₁₋₆ aliphatic is optionally substituted with 0-2 J″. In some embodiments, said C₁₋₆ aliphatic is unsubstituted.

In some embodiments, each R⁶ is independently selected from hydrogen or C₁₋₄ aliphatic group optionally substituted with 0-3 J⁶; or two R⁶ groups on the same nitrogen atom are taken together with the nitrogen atom to form a 4-6 membered heterocyclyl or heteroaryl ring, wherein said heterocyclyl or heteroaryl ring is optionally substituted with 0-4 J⁶. In some embodiments, two R⁶ groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring, wherein said heterocyclyl or heteroaryl ring is optionally substituted with 0-4 J⁶.

One embodiment of this invention is represented by formula Ia:

Another embodiment of this invention is represented by formula Ib:

Another embodiment of this invention is represented by formula Ic:

Another embodiment of this invention is represented by formula Id:

Another embodiment of this invention is represented by formula Ie:

Another embodiment of this invention is represented by formula If:

wherein R₂ and R^(2′) are taken together with their intervening atoms to form a substituted or unsubstituted benzo or pyrido ring.

In some embodiments, the variables are as depicted in the compounds of Table 1.

In some embodiments, the compounds of this invention are as represented in Table 1:

TABLE 1 I-1

I-2

I-3

General Synthetic Methodology

The compounds of this invention may be prepared in general by methods such as those depicted in the general schemes below, and the preparative examples that follow. Unless otherwise indicated, all variables in the following schemes are as defined herein.

Scheme 1 above shows a general synthetic route that is used for preparing the compounds 5. Compounds of formula 5 can be prepared from intermediate 3. The formation of intermediate 3 is achieved by reacting diethyl malonate with the corresponding amidine in the presence of EtONa as a base in refluxing ethanol. Then the crude is treated with POCl₃ to yield dichloropyrimidine intermediate 3. Then the dichloropyrimidine intermediate is sequentially treated with heterocyclic amines and azetidine derivatives to yield final compounds 5. These two reactions sequence are amenable to a variety of heterocyclic amines and substituted azetidines.

The present invention provides compounds and compositions that are useful as inhibitors of protein kinases. In some embodiments, the protein kinases are GSK-3 kinases.

As inhibitors of protein kinases, the compounds and compositions of this invention are particularly useful for treating or lessening the severity of a disease, condition, or disorder where a protein kinase is implicated in the disease, condition, or disorder. In one aspect, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where a protein kinase is implicated in the disease state. In another aspect, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where inhibition of enzymatic activity is implicated in the treatment of the disease. In another aspect, this invention provides a method for treating or lessening the severity of a disease, condition, or disorder with compounds that inhibit enzymatic activity by binding to the protein kinase. Another aspect provides a method for treating or lessening the severity of a kinase disease, condition, or disorder by inhibiting enzymatic activity of the kinase with a protein kinase inhibitor.

In some embodiments, said protein kinase inhibitor is GSK-3.

As inhibitors of protein kinases, the compounds and compositions of this invention are also useful in biological samples. One aspect of the invention relates to inhibiting protein kinase activity in a biological sample, which method comprises contacting said biological sample with a compound of formula I or a composition comprising said compound. The term “biological sample”, as used herein, means an in vitro or an ex vivo sample, including, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of protein kinase activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, and biological specimen storage.

Another aspect of this invention relates to the study of protein kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such protein kinases; and the comparative evaluation of new protein kinase inhibitors. Examples of such uses include, but are not limited to, biological assays such as enzyme assays and cell-based assays.

The activity of the compounds as protein kinase inhibitors may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the kinase activity or ATPase activity of the activated kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and may be measured either by radiolabelling the inhibitor prior to binding, isolating the inhibitor/kinase complex and determining the amount of radiolabel bound, or by running a competition experiment where new inhibitors are incubated with the kinase bound to known radioligands.

Another aspect of this invention provides compounds that are useful for the treatment of diseases, disorders, and conditions including, but not limited to, autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immunologically-mediated diseases, immunodeficiency disorders, immunomodulatory or immunosuppressive disorder, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, neurotrophic factor, cardiovascular diseases, hormone related diseases, diabetes, allergies, asthma, and Alzheimer's disease. Another aspect of this invention provides compounds that are inhibitors of protein kinases, and thus are useful for the treatment of the diseases, disorders, and conditions, along with other uses described herein.

Another aspect provides pharmaceutically acceptable compositions comprising any of the compounds described herein and optionally comprising a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

One aspect of this invention provides a method for the treatment or lessening the severity of a disease, disorder, or condition selected from an autoimmune disease, an inflammatory disease, a proliferative or hyperproliferative disease, such as cancer, an immunologically-mediated disease, an immunodeficiency disorders, a bone disease, a metabolic disease, a neurological or neurodegenerative disease, a cardiovascular disease, allergies, diabetes, asthma, Alzheimer's disease, or a hormone related disease, comprising administering an effective amount of a compound, or a pharmaceutically acceptable composition comprising a compound, to a subject in need thereof.

The term “cancer” includes, but is not limited to, the following cancers: epidermoid Oral: buccal cavity, lip, tongue, mouth, pharynx; Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel or small intestines (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel or large intestines (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colon-rectum, colorectal; rectum, Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast; Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma] hairy cell; lymphoid disorders; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis, Thyroid gland: papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, undifferentiated thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma; and Adrenal glands: neuroblastoma. Thus, the term “cancerous cell” as provided herein, includes a cell afflicted by any one of the above-identified conditions. In some embodiments, the cancer is selected from colorectal, thyroid, or breast cancer.

The term “Aurora-mediated condition” or “Aurora-mediated disease” as used herein means any disease or other deleterious condition in which Aurora (Aurora A, Aurora B, and Aurora C) is known to play a role. Such conditions include, without limitation, cancer such as colorectal, thyroid, and breast cancer; and myeloproliferative disorders, such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myelogenous leukaemia (CML), chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mast cell disease.

In certain embodiments, an “effective amount” of the compound or pharmaceutically acceptable composition is that amount effective in order to treat said disease. The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of said disease. In some embodiments, said disease is chosen from allergic or type I hypersensitivity reactions, asthma, diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-associated dementia, bipolar disorder, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), schizophrenia, leukocytopenia, cardiomyocyte hypertrophy, reperfusion/ischemia, stroke, baldness, transplant rejection, graft versus host disease, rheumatoid arthritis, and solid and hematologic malignancies. In some embodiments, said disease is chosen from diabetes, bipolar disorder, schizophrenia, stroke, Huntington's disease, leukocytopenia and cardiomyocyte hypertrophy.

In other embodiments of this invention, said disease is a protein-kinase mediated condition. In some embodiments, said protein kinase in GSK-3.

The term “protein kinase-mediated condition”, as used herein means any disease or other deleterious condition in which a protein kinase plays a role. Such conditions include, without limitation, autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immunologically-mediated diseases, immuno-deficiency disorders, immunomodulatory or immunosuppressive disorder, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, hormone related diseases, diabetes, allergies, asthma, and Alzheimer's disease.

The term “GSK-3-mediated condition”, as used herein means any disease or other deleterious condition in which GSK-3 plays a role. Such conditions include, without limitation, diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-associated dementia, bipolar disorder, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), schizophrenia, leukocytopenia, cardiomyocyte hypertrophy, stroke, and rheumatoid arthritis.

In some embodiments, the compounds are used to treat diabetes by promoting beta cell regeneration.

In other embodiments, the compounds are used to treat stroke recovery. In some cases, the compounds are used in post-stroke administration. The length of treatment can range from 1 month to one year.

In yet other embodiments, the compounds are used to treat osteoporosis by osteoblastogenesis.

It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable salt or pharmaceutically acceptable derivative thereof.

It should be understood that this invention includes mixtures/combinations of different pharmaceutically acceptable salts and also mixtures/combinations of compounds in free form and pharmaceutically acceptable salts.

As described herein, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.

Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

The protein kinase inhibitors or pharmaceutical salts thereof may be formulated into pharmaceutical compositions for administration to animals or humans. These pharmaceutical compositions, which comprise an amount of the protein inhibitor effective to treat or prevent a protein kinase-mediated condition and a pharmaceutically acceptable carrier, are another embodiment of the present invention. In some embodiments, said protein kinase-mediated condition is a GSK-3-mediated condition. In some embodiments, a GSK-3-mediated condition.

The exact amount of compound required for treatment will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar—agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

In addition to the compounds of this invention, pharmaceutically acceptable derivatives or prodrugs of the compounds of this invention may also be employed in compositions to treat or prevent the above-identified disorders.

A “pharmaceutically acceptable derivative or prodrug” means any pharmaceutically acceptable ester, salt of an ester or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. Particularly favoured derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.

Pharmaceutically acceptable prodrugs of the compounds of this invention include, without limitation, esters, amino acid esters, phosphate esters, metal salts and sulfonate esters.

Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include, but are not limited to, lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

The amount of protein kinase inhibitor that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of inhibitor will also depend upon the particular compound in the composition.

According to another embodiment, the invention provides methods for treating or preventing a protein kinase-mediated condition (in some embodiments, a GSK-3-mediated condition) comprising the step of administering to a patient one of the above-described pharmaceutical compositions. The term “patient”, as used herein, means an animal, preferably a human.

In some embodiments, that method is used to treat or prevent a condition selected from cancers such as cancers of the breast, colon, prostate, skin, pancreas, brain, genitourinary tract, lymphatic system, stomach, larynx and lung, including lung adenocarcinoma and small cell lung cancer; stroke, diabetes, myeloma, hepatomegaly, cardiomegaly, Alzheimer's disease, cystic fibrosis, and viral disease, or any specific disease described above.

In other embodiments, that method is used to treat or prevent a condition selected from diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-associated dementia, bipolar disorder, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), schizophrenia, leukocytopenia, cardiomyocyte hypertrophy, stroke, or rheumatoid arthritis.

In some embodiments, that method is used to treat diabetes by promoting beta cell regeneration.

In other embodiments, that method is used to treat stroke recovery. In some cases, the compositions are used in post-stroke administration. The length of treatment can range from 1 month to one year.

In yet other embodiments, the compositions are used to treat osteoporosis by osteoblastogenesis.

Another aspect of the invention relates to inhibiting protein kinase activity in a patient, which method comprises administering to the patient a compound of formula I or a composition comprising said compound.

Depending upon the particular protein kinase-mediated conditions to be treated or prevented, additional drugs, which are normally administered to treat or prevent that condition, may be administered together with the inhibitors of this invention. For example, chemotherapeutic agents or other anti-proliferative agents may be combined with the protein kinase inhibitors of this invention to treat proliferative diseases.

Those additional agents may be administered separately, as part of a multiple dosage regimen, from the protein kinase inhibitor—COntaining compound or composition. Alternatively, those agents may be part of a single dosage form, mixed together with the protein kinase inhibitor in a single composition.

In some embodiments, said protein kinase inhibitor is a GSK-3 kinase inhibitor.

This invention may also be used in methods other than those involving administration to a patient.

The compounds of this invention may be prepared in general by methods known to those skilled in the art. Those compounds may be analyzed by known methods, including but not limited to LCMS (liquid chromatography mass spectrometry) and NMR (nuclear magnetic resonance). Compounds of this invention may be also tested according to these examples. It should be understood that the specific conditions shown below are only examples, and are not meant to limit the scope of the conditions that can be used for making, analyzing, or testing the compounds of this invention. Instead, this invention also includes conditions known to those skilled in that art for making, analyzing, and testing the compounds of this invention.

Examples

As used herein, the term “Rt(min)” refers to the HPLC or LCMS retention time, in minutes, associated with the compound.

Unless otherwise indicated, the HPLC method utilized to obtain the reported retention time is as follows:

-   -   Column: ACE C8 column, 4.6×150 mm     -   Gradient: 0-100% acetonitrile+methanol 60:40 (20 mM Tris         phosphate)     -   Flow rate: 1.5 mL/minute     -   Detection: 225 nm.

Mass spec. samples were analyzed on a MicroMass Quattro Micro mass spectrometer operated in single MS mode with electrospray ionization. Samples were introduced into the mass spectrometer using chromatography. Mobile phase for all mass spec. analyses consisted of 10 mM pH 7 ammonium acetate and a 1:1 acetonitrile-methanol mixture, column gradient conditions are 5%-100% acetonitrile-methanol over 3.5 mins gradient time and 5 mins run time on an ACE C8 3.0×75 mm column. Flow rate is 1.2 ml/min.

¹H-NMR spectra were recorded at 400 MHz using a Bruker DPX 400 instrument. The following compounds of formula I were prepared and analyzed as follows.

Intermediate 1

Cyclohexanecarboximidamide hydrochloride

Hydrogen chloride gas was bubbled through a solution of cyclohexanecarbonitrile (60 g, 550mmol) in a mixture of MeOH (33 ml) and Et₂O (150 ml) with stirring at 0° C. After bubbling for 1 h the flask was removed to the fridge where it remained overnight. The RM was then diluted with Et₂O and the resulting solid filtered. The crude solid was dissolved in an ethanol (400 mL) and 2N ammonia in ethanol (100 mL) mixture. Ammonia gas was bubbled through this suspension for 1 h before the reaction mixture was removed to the fridge overnight. The reaction mixture was filtered and the sticky solid washed into a flask with methanol. The mixture was concentrated in-vacuo, Et₂O added and the solid filtered. The solid was redissolved in methanol and concentrated until a solid began to precipitate at which stage Et₂O was added. The solid was then filtered and placed on the high-vacuum overnight to give the title compound as a solid (87.8 g, 98%). ¹H NMR: (DMSO) 1.00-1.88 (10H, m) , 2.35-2.57 (1H, m), 8.86 (1H, s), 9.02 (1H, s).

Intermediate 2

2-cyclohexylpyrimidine-4,6-diol

A solution of sodium ethoxide in ethanol [previously prepared by dissolving sodium (2.12 g, 92.2 mmol) in ethanol (200 mL)] was treated with diethyl malonate (6.1 mL, 40.2 mmol) with stirring at ambient temperature. A solution of cyclohexanecarboximidamide hydrochloride (5 g, 31 mmol) in ethanol (100 mL) was then added dropwise with stirring at room temperature. On completion of addition the reaction mixture was heated at reflux for 8 h and allowed to stand overnight. The reaction mixture was concentrated in vacuo, water added and the pH adjusted to pH 7-8 using 2N HCl. The resulting solid formed was filtered and washed with diethyl ether to give the title compound as a solid (5.53 g, 93%). MS (ES+) m/e=195. ¹H NMR: (DMSO) 1.09-1.81 (10H, m), 2.40-2.53 (1H, m), 5.09 (1H, s), 11.61 (2H, brs).

Intermediate 3

4,6-Dichloro-2-cyclohexylpyrimidine

A mixture containing 2-cyclohexylpyrimidine-4,6-diol (5.53 g, 28.5 mmol) and phosphoryl chloride (70 mL, 751 mmol) was heated at reflux for 3 h before being cooled to room temperature and concentrated in vacuo. The semi-solid formed was then treated with ice-water, sNaHCO₃, extracted with Et₂O and dried (Na₂SO₄) and concentrated in-vacuo. The resulting residue was purified by column chromatography (eluting with EtOAc/Petrol, 1/9) to give the title compound as an oil (5.74 g, 87%). MS (ES+) m/e=231. ¹H NMR: (DMSO) 1.15-2.00 (10H, m), 2.70-2.84 (1H, m), 7.86 (1H, s).

Intermediate 4

N-(6-chloro-2-cyclohexylpyrimidin-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine

A mixture cooled to −60° C. containing 4,6-dichloro-2-cyclohexylpyrimidine (505 mg, 2.19 mmol), 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine (400 mg, 2.63 mmol) and THF (20 mL) was treated drop wise with a 1M solution of lithium bis(trimethylsilyl)amide in THF (5.46 mL, 5.46 mmol). The reaction mixture was then allowed to warm to 0° C. over 1 h before water was added. The reaction mixture partitioned between water and EtOAc, washed with sat. NaCl solution and dried (Na₂SO₄) and concentrated in-vacuo. The resulting residue was purified by column chromatography (eluting with MeOH/DCM, 5/95) to give the title compound as a solid (380 mg, 50%). MS (ES+) m/e=347. ¹H NMR: (DMSO) 1.10-1.96 (10H, m), 2.56-2.69 (1H, m), 7.65 (1H, brs), 8.27-8.39 (1H, m), 8.58 (1H, s), 10.72 (1H, s), 13.34 (1H, s).

Example 1

N-(6-(azetidin-1-yl)-2-cyclohexylpyrimidin-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine

A mixture containing N-(6-chloro-2-cyclohexylpyrimidin-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine (78 mg, 0.22 mmol), N, N-diisopropylethylamine (158 μL, 0.91 mmol), azetidine (45 μL, 0.67 mmol) and n-butanol (6 mL) was heated at 125° C. for 20 min in the microwave. The reaction mixture was cooled to room temperature and the resulting solid was filtered and the solid washed with Et₂O, sNH₄Cl and Et₂O. The resulting solid was air dried to give the title compound as a white solid (48 mg, 58%). MS (ES+) m/e=368. ¹H NMR: (DMSO) 1.08-1.92 (10H, m), 2.26-2.58 (3H, m), 3.89-4.06 (4H, m), 6.50 (1H, brs), 8.32-8.62 (2H, m), 9.79 (1H, s), 13.03 (1H, s)

The follow compounds were prepared according to the method used to prepare compound I-1.

LCMS Compound # LCMS Rt (min) NMR

I-1 368.00 3.92 (400 MHz, DMSO) 1.08-1.92 (10H, m), 2.26-2.58 (3H, m), 3.89-4.06 (4H, m), 6.50 (1H, brs), 8.32-8.62 (2H, m), 9.79 (1H, s), 13.03 (1H, s).

I-2 313.0 3.72 (400 MHz, DMSO) 1.13-1.88 (10H, m), 2.13-2.60 (6H, m), 3.86-3.94 (4H, m), 5.91 (1H, brs), 6.12 (1H, brs), 8.98 (1H, brs), 11.81 (1H, brs).

I-3 367.0 3.97 (400 MHz, DMSO) 1.12-1.89 (10H, m), 2.26-2.54 (3H, m), 3.91-4.00 (4H, m), 6.55 (1H, s), 7.17-7.29 (1H, m), 7.38-7.46 (1H, m), 7.84-7.96 (1H, m), 9.57 (1H, s), 12.44 (1H, s).

Example 2

The overall synthetic scheme for the synthesis of 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine (5a) is depicted below.

2-chloro-5-fluoronicotinic acid (6a)

To a round-bottomed flask under a N₂ atmosphere were added degassed DMF (270 mL), Pd(OAc)₂ (0.05 eq, 2.7 g, 11.9 mmol), PPh₃ (0.1 eq, 6.2 g, 23.8 mmol) and degassed Et₃N (6 eq, 200 mL, 1428.6 mmol). The mixture was stirred 20 minutes then HCOOH (3 eq, 28 mL, 714.3 mmol) was added followed after 5 minutes by 2,6-dichloro-5-fluoronicotinic acid (50 g, 238.1 mmol) and the mixture was stirred at 50° C. The reaction was followed by analysis (1H NMR) of a worked-up aliquot. When all starting material was consumed (24 h), the mixture was cooled to 0° C. and water (500 mL) was added. After 20 minutes, The mixture was filtered through a pad of Celite that was rinsed with water. The mixture was basified to pH 9 with 30% aq. NaOH and washed with EtOAc (2×). HCl (12 N) was added slowly to pH 1 and the solution was saturated with NaCl. The mixture was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried (Na₂SO₄) and concentrated under reduced pressure to give 37 g (88%) of a beige solid used in the next step without further purification.

¹H NMR (DMSO-d₆, 300 MHz): δ 8.16 (dd, 1H); 8.58 (d, 1H)

2-Chloro-5-fluoronicotinamide (3a)

To a solution of 2-chloro-5-fluoronicotinic acid 6a (50 g, 285 mmol) and DMF (2 mL, 28 mmol) in DCM (400 mL) at 0° C. was added oxalyl chloride (64 mL, 741 mmol) dropwise. The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The resulting yellow liquid was dissolved in 1,4-dioxane (600 mL), cooled at 0° C. and NH₃(g) was bubbled through the solution for 30 minutes. The mixture was stirred at room temperature overnight. The resulting mixture was filtered and the filtrate was concentrated to give compound 3a (44 g, 89%) as a beige solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 7.84 (s, 1H), 7.96 (dd, 1H), 8.09 (s, 1H), 8.49 (d, 1H).

2-Chloro-5-fluoronicotinonitrile (4a)

A suspension of crude compound 3a (65 g, 372.4 mmol) and Et₃N (114 mL, 819.2 mmol) in DCM (700 mL) was cooled to 0° C. and TFAA (57 mL, 409.6 mmol) and was added dropwise. The resulting yellow solution was stirred for 90 minutes at 0° C., diluted with DCM, washed with sat. aq. NaHCO₃ and brine, and dried (Na₂SO₄). The mixture was filtered and concentrated. Kugel Rohr distillation of the residue (˜70° C./1 mbar) gave 50 g (86%) of compound 4a as a beige solid. Compound 4a can also be purified by column chromatography (SiO₂, 8:1 heptane: EtOAc). ¹H NMR (CDCl₃, 300 MHz): δ 7.78 (dd, 1H); 8.49 (d, 1H).

5-Fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine (5a)

To a solution of compound 4a (50 g, 321.7 mmol) in 1-butanol (1 L) was added hydrazine monohydrate (150 mL, 3.2 mol), and the mixture was refluxed for 4 h. The mixture was cooled to room temperature and concentrated. The precipitate was successively washed on filter with water (2×) and Et₂O (2×) and dried in vacuo overnight to give compound 5a (44 g, 88%) as a yellow solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 5.53 (s, 2H); 7.94 (dd, 1H); 8.35 (dd, 1H); 12.02 (s, 1H).

Example 3 GSK-3 Inhibition Assay

Compounds of the present invention were screened for their ability to inhibit GSK-3β (AA 1-420) activity using a standard coupled enzyme system (Fox et al., Protein Sci. 1998, 7, 2249). Reactions were carried out in a solution containing 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl, 300 μM NADH, 1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were 20 μM ATP (Sigma Chemicals, St Louis, Mo.) and 300 μM peptide (American Peptide, Sunnyvale, Calif.). Reactions were carried out at 30° C. and 20 nM GSK-3β. Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 300 μM NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactate dehydrogenase.

An assay stock buffer solution was prepared containing all of the reagents listed above with the exception of ATP and the test compound of the present invention. The assay stock buffer solution (175 μl) was incubated in a 96 well plate with 5 μl of the test compound of the present invention at final concentrations spanning 0.002 μM to 30 μM at 30° C. for 10 min. Typically, a 12-point titration was conducted by preparing serial dilutions (from 10 mM compound stocks) with DMSO of the test compounds of the present invention in daughter plates. The reaction was initiated by the addition of 20 μl of ATP (final concentration 20 μM). Rates of reaction were obtained using a Molecular Devices Spectramax plate reader (Sunnyvale, Calif.) over 10 min at 30° C. The K_(i) values were determined from the rate data as a function of inhibitor concentration. Compounds I-1 and I-2 were found to inhibit GSK-3 at a Ki value of <50 nM. Compound I-3 was found to inhibit GSK-3 at a Ki value between 50 and 100 nM.

While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize or encompass the compounds, methods, and processes of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims. 

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: Ht is

Ring D is a 4-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from a heterocyclyl or a carbocyclyl ring; said heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted with oxo or —R⁵, and any substitutable ring nitrogen is independently substituted with —R⁴; X is sulfur, oxygen, or NR^(2′); Y is nitrogen or CR₂; Z¹ and Z² are each independently N or CR⁹; provided that at least one of Z¹ or Z² is N; R^(X) is T¹-R³; R^(Y) is T²-R¹⁰; R² and R^(2′) are independently selected from —R or -T³-W—R⁶; or R² and R^(2′) are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R² and R^(2′) is substituted with halo, oxo, —CN, —NO₂, —R₇, or —V—R⁶, and any substitutable nitrogen on said ring formed by R² and R^(2′) is substituted with R⁴; each T, T¹ and T³ is independently a bond or a C₁₋₄ alkylidene chain; T² is independently a bond or a C₁₋₄ alkylidene chain wherein up to three methylene units of the alkylidene chain are optionally replaced by —O—, —C(═O)—, —S(O)—, —S(O)₂—, —S—, or —N(R₄)—; R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂R″, —N(R⁴)N(R⁴)₂, —C(═NH)N(R⁴)₂, —C(═NH)—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂; each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴ on the same nitrogen are taken together to form a 3-8 membered heterocyclyl or heteroaryl ring; each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂R″, —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂; p1 V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R₆)—, —C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R₆)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—; W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)₂OC(O)—, —C(R⁶)₂OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—; each R⁶ is independently selected from hydrogen or C₁₋₄ aliphatic group optionally substituted with 0-3 J⁶; or two R⁶ groups on the same nitrogen atom are taken together with the nitrogen atom to form a 4-6 membered heterocyclyl or heteroaryl ring, wherein said heterocyclyl or heteroaryl ring is optionally substituted with 0-4 J⁶; each R⁷ is independently selected from hydrogen or R″; or two R⁷ on the same nitrogen are taken together with the nitrogen to form a 4-8 membered heterocyclyl or heteroaryl ring, wherein said heterocyclyl or heteroaryl ring is optionally substituted with 0-4 J⁷; each R⁹ is —R′, -halo, —OR′, —C(═O)R′, —CO₂R′, —COCOR′, COCH₂COR′, —NO₂, —CN, —S(O)R′, —S(O)₂R′, —SR′, —N(R′)₂, —CON(R′)₂, —SO₂N(R′)₂, —OC(═O)R′, —N(R′)COR′, —N(R′)CO₂(C₁₋₆ aliphatic), —N(R′)N(R′)₂, —N(R′)CON(R′)₂, —N(R′)SO₂N(R′)₂, —N(R′)SO₂R′, —OC(═O)N(R′)₂, ═NN(R′)₂, ═N—OR′, or ═O; each R¹⁰ is a 4-membered heterocyclic ring containing 1-2 heteroatoms selected from O, NR¹¹, and S; each R¹⁰ is optionally substituted with 0-3 occurrences of J; each R¹¹, is —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷; each R is independently selected from hydrogen or an optionally substituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 4-10 ring atoms; each R is optionally substituted with 0-5 R⁹; each R′ is independently hydrogen or a C₁₋₆ aliphatic group optionally substituted with 0-4 J′; or two R′, together with the atom(s) to which they are attached, form a 3-6 membered carbocyclyl or heterocyclyl wherein said carbocyclyl or heterocyclyl is optionally substituted with 0-4 J′; each R″ is independently C₁₋₆ aliphatic optionally substituted with 0-4 J″; each J′ and J″ is independently NH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, halogen, C₁₋₄aliphatic, OH, O(C₁₋₄aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄ aliphatic), or haloC₁₋₄aliphatic; each J, J⁶, and J⁸ is independently -halo, —OR, oxo, C₁₋₆ aliphatic, —C(═O)R, —CO₂R, —COCOR, COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, ═NN(R⁴)₂, ═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂; each J⁷ is independently -halo, —OR, oxo, C₁₋₆ aliphatic, —C(═O)R, —CO₂R, —COCOR, COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R¹²)₂, —CON(R¹²)₂, —SO₂N(R¹²)₂, —OC(═O)R, —N(R¹²)COR, —N(R¹²)CO₂(C₁₋₆ aliphatic), —N(R¹²)N(R²)₂, ═NN(R¹²)₂, ═N—OR, —N(R¹²)CON(R¹²)₂, —N(R¹²)SO₂N(R¹²)₂, —N(R¹²)SO₂R, or —OC(═O)N(R¹²)₂; or 2 J groups, 2 J⁶ groups, 2 J⁷ groups, or 2 J⁸ groups, on the same atom or on different atoms, together with the atom(s) to which they are bound, form a 3-8 membered saturated, partially saturated, or unsaturated ring having 0-2 heteroatoms selected from O, N, or S; R¹² is independently selected from hydrogen or R″; or two R₁₂ on the same nitrogen are taken together with the nitrogen to form a 4-8 membered heterocyclyl or heteroaryl ring, wherein said heterocyclyl or heteroaryl ring is optionally substituted with 0-4 J″.
 2. The compound according to claim 1 wherein Ht is


3. The compound according to claim 1 wherein Ht is


4. The compound according to claim 3, wherein X is N. 5-6. (canceled)
 7. The compound according to claim 3, wherein X is S and Y is CR².
 8. The compound according to claim 1, wherein Z¹ and Z² are both nitrogen.
 9. The compound according to claim 1, wherein Z¹ is nitrogen and Z² is CH.
 10. The compound according to claim 1, wherein Z¹ is CR⁹ and Z² is nitrogen.
 11. The compound according to claim 8, wherein R^(2′) is hydrogen or methyl.
 12. The compound according to claim 11, wherein R^(2′) is hydrogen.
 13. The compound according to claim 11, wherein R² is T³-W—R₆ or R, wherein W is —C(R⁶)₂O—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)₂OC(O)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, or —CON(R⁶)—, and R is an optionally substituted group selected from C₁₋₆ aliphatic or phenyl.
 14. The compound according to claim 11, wherein R² is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.
 15. The compound according to claim 14, wherein R² is hydrogen or a substituted or unsubstituted group selected from aryl or a C₁₋₆ aliphatic group.
 16. The compound according to claim 8, wherein R² and R^(2′) are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring.
 17. The compound according to claim 16, wherein R² and R^(2′) are taken together with their intervening atoms to form a substituted or unsubstituted benzo or pyrido ring.
 18. The compound according to claim 17, wherein said benzo or pyrido ring is substituted with 1-2 halo substituents.
 19. The compound according to claim 8, wherein R^(X) is hydrogen, C₁₋₄aliphatic, or halo.
 20. The compound according to claim 19, wherein R^(X) is hydrogen, methyl, ethyl, cyclopropyl, or isopropyl.
 21. The compound according to claim 20, wherein R^(X) is hydrogen.
 22. The compound according to claim 8, wherein R^(Y) is represented by formula ii-a:


23. The compound according to claim 8, wherein R^(Y) is T²-R¹⁰ wherein T² is a bond.
 24. The compound according to claim 23, wherein R¹⁰ is an optionally substituted azetidine.
 25. The compound according to claim 24, wherein R^(Y) is represented by formula i:


26. The compound according to claim 24, wherein R^(Y) is represented by formula iii:


27. The compound according to claim 8, wherein Ring D is an optionally substituted ring selected from piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, or isoquinolinyl.
 28. The compound according to claim 8, wherein Ring D is optionally substituted tetrahydronaphthyl, benzodioxinyl, indanyl, indolinyl, or isoquinolinyl.
 29. The compound according to claim 8, wherein Ring D is cyclohexyl.
 30. The compound of claim 1 selected from the following:


31. A composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
 32. The composition according to claim 31, additionally comprising a therapeutic selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.
 33. A method of inhibiting GSK-3 activity in an ex vivo or in vitro biological sample with a compound according to claim
 1. 34. A method of treating or lessening the severity of a disease or condition selected from diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-associated dementia, bipolar disorder, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), schizophrenia, leukocytopenia, cardiomyocyte hypertrophy, stroke, and rheumatoid arthritis, comprising the step of administering to said patient a compound according to claim
 1. 35. The method of claim 34, wherein said disease is stroke.
 36. The method of claim 34, wherein said disease is diabetes.
 37. The method of claim 34, wherein said disease is schizophrenia.
 38. The method of claim 34, wherein said disease is bipolar disorder.
 39. The method of claim 34, comprising the additional step of administering to said patient an additional therapeutic agent selected from an agent for treating diabetes, an agent for treating Alzheimer's disease, an agent for treating Huntington's disease, an agent for treating Parkinson's disease, an agent for treating AIDS-associated dementia, an agent for treating bipolar disorder, an agent for treating amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), an agent for treating multiple sclerosis (MS), an agent for treating schizophrenia, an agent for treating leukocytopenia, an agent for treating cardiomyocyte hypertrophy, an agent for treating stroke, and an agent for treating rheumatoid arthritis, wherein: a. said additional therapeutic agent is appropriate for the disease being treated; and b. said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.
 40. A method of treating or lessening the severity of a disease or condition selected from leukocytopenia, diabetes, stroke recovery, or osteoporosis, comprising the step of administering to said patient a compound according to claim
 1. 41. The method of claim 40, comprising the additional step of administering to said patient an additional therapeutic agent selected from an agent for treating diabetes, an agent for treating leukocytopenia, an agent for treating stroke recovery, or an agent for treating osteoporosis. 